Tetra-aza macrocycles and metal complexes thereof

Details Tetra-aza macrocycles and metal complexes thereof Tetra-aza macrocycles and metal complexes thereof

1990-08-31

2004-08-10

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C530S391100, C530S391500, C424S009363

Reexamination Certificate

active

06774228

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to functionalised tetra-aza macrocycles, to metal complexes thereof, to conjugate compounds containing the functionalised tetra-aza macrocycles and metal complexes thereof and to their use in diagnosis and therapy.
BACKGROUND TO THE INVENTION
The attachment of metal ions to proteins, peptides and other, smaller molecules is a fast expanding technology, which has numerous proven and potential applications in research, in industry and, particularly, in medicine.
In recent years, much of the impetus behind the development of this technology has been the ability to link metal ions to antibodies, especially monoclonal antibodies. Such metal labelled antibodies have found a widespread use, especially in medicine, where they have been employed, for example, to target the metal ion to a specific tissue type, both in vitro and in vivo. Thus, metal labelled antibodies have applications in locating specific tissue types (e.g. employing computer-aided tomographic techniques where the metal ion is in some way detectable) and in the treatment of cell disorders (e.g treating mammalian tumours where the metal ion is a cytotoxic radionuclide).
Conventionally, attachment of the metal ion to a protein such as an antibody has been achieved by complexation by an acyclic chelate such as a substituted diethylenetriaminepentaacetic acid [Gansow O. A. et al, Inorg. Chem., (1986), 25, 2772] or ethylenediaminetetraacetic acid [Meares, C. F. et al, Acc. Chem. Res., (1984), 17, 202] covalently linked to the antibody. Such acyclic complexes however tend to be unstable in vivo either as a result of acid-catalysed decomplexation or competitive chelate binding by Ca
2+
or Zn
2+
in serum, or as a result of competition from transferrin [Moerlein, S. M. et al, Int. J. Nuc. Med. Biol., (1981) 8, 277]. The lack of stability can result in uncomplexed metal atoms in the body which have a cytotoxic effect on healthy tissue (e.g. bone marrow) or which markedly reduce the signal-to-noise ratio of an imaging technique.
A possible alternative to the use of acyclic chelates in the labelling of antibodies is the use of macrocyclic ligands, which has been suggested in broad terms [Gansow O. A. et al. Am. Chem. Soc. Symp. Ser., (1984), 241, 215; UK Patent Specification Publication No. 2122641; and Moi M. K. et al, Anal. Biochem., (1985), 148, 249-253].
We have now found a new class of functionalised tetra-aza macrocyles, members of which are able to form more kinetically inert complexes with metal ions than are chelating agents conventionally in use for the attachment of metal ions to proteins and other molecules. The macrocycles of the invention are particularly useful for attachment to proteins, especially antibodies, to provide conjugate compounds capable of binding metals to give complexes which are advantageously stable in vivo.
SUMMARY OF THE INVENTION
Thus, according to one aspect of the present invention we provide a compound of general formula (1):
wherein
m and n, which may be the same or different, is each zero or an integer 1, 2, or 3;
d is zero or an integer 1, 2 or 3;
q is zero or an integer from 1 to 6 inclusive;
R, R
1
, R
2
and R
3
, which may be the same or different, is each a hydrogen atom or an alkyl, alkoxyalkyl, —CO
2
H, —SO
3
H, —PO
3
H
2
or aryl group;
L is a covalent bond or a linker group;
Z is a hydrogen atom or a reactive functional group, with the proviso that when L is a covalent bond Z is a reactive functional group;
and metal complexes and/or salts thereof.
In the compounds of formula (1), alkyl groups represented by R, R
1
, R
2
and R
3
may be for example C
1-6
alkyl groups such as methyl or ethyl groups. Alkoxyalkyl groups represented by R, R
1
, R
2
or R
3
may be for example C
1-3
alkoxyC
1-3
alkyl groups e.g. methoxymethyl. When R, R
1
, R
2
or R
3
is an aryl group it may be for example a substituted phenyl group, such as a group of formula
(where R
4
is a hydrogen atom or a C
1-6
alkyl, e.g. methyl, C
1-3
alkoxy
1-3
alkyl, e.g. methoxymethyl, or C
6-12
aryl, e.g. phenyl group).
In general, compounds of formula (1) in which R, R
1
, R
2
and R
3
are the same are preferred. Compounds of this type in which q is an integer from 1 to 6 inclusive, particularly an integer 1, and R
1
, R
2
and R
3
are —SO
3
H, —PO
3
H
2
or, in particular, —CO
2
H, are especially preferred.
In the compounds of formula (1), it will be appreciated that the nature of the group L when it is a linker group may be varied widely without substantially affecting the usefulness of compounds of formula (1) and the metal complexes thereof. Thus L may be any suitable organic radical and may be for example an optionally substituted aliphatic hydrocarbyl chain, optionally interrupted by one or more heteroatoms selected from —O— or —S— or by one or more —N(R
5
)— (where R
5
is a hydrogen atom or a C
1-6
alkyl group), —CON(R
5
)—, —N(R
5
)CO—, cycloalkylene, aromatic, or heteroaromatic groups.
In the above definition, and in the same context whenever it appears below, the term “interrupted by” as applied to cycloaliphatic or aromatic groups is to be understood to also mean that these particular groups may additionally be present linked to the terminal carbon atom of the hydrocarbyl chain represented by L, at the opposite end of the chain to the carbon atom attached to the macrocycle.
Thus, for example, L may be an optionally substituted straight or branched C
1-20
alkylene, C
2-20
alkenylene, or C
2-20
alkynylene chain, optionally interrupted by one or more —O— or —S— atoms or C
5-8
cycloalkylene (e.g. cyclopentylene or cyclohexylene), C
6-12
aromatic (e.g phenylene or substituted phenylene), C
5-10
heteroaromatic (e.g furanyl, pyridyl), —N(R
5
)—, —CON(R
5
)— or —N(R)
5
CO— groups.
Examples of substituents which may be present on the chain L include halogen atoms, e.g. fluorine, chlorine, bromine, or iodine atoms or groups selected from C
1-6
alkoxy (e.g methoxy or ethoxy), hydroxy, nitro, —N(R
6
)(R
7
), [where R
6
is a hydrogen atoms or a C
1-6
alkyl group and R
7
is a C
1-6
alkyl group; e.g. —NHCH
3
or —N(CH
3
)
2
], or substituted amido, e.g. a group of formula —(CH
2
)
n
CON(R
8
)(R
9
) [where n is zero or an integer 1 to 4 inclusive, R
8
is a hydrogen atom or a C
1-6
alkyl group, e.g. methyl and R
9
is an optionally substituted C
1-6
alkyl group].
Substituted alkyl groups represented by R
9
include for example C
1-6
alkyl groups substituted by one or more halogen atoms, or nitro, amino or hydroxy groups.
In general, in compounds of formula (1) the linker group is preferably an optionally substituted C
1-10
alkylene, (especially C
1-6
alkylene such as methylene, ethylene, propylene butylene, pentylene or hexylene) C
2-10
alkenylene or C
2-10
alkynylene chain optionally interrupted by one or more —O— or —S— atoms or cyclohexylene, phenylene, substituted phenylene, —NH—, —N(CH
3
)—, —CONH—, —CON(CH
3
)— —NHCO— or —N(CH
3
)CO— groups.
Particular examples of linker groups represented by L include, for example, —(CH
2
)
d
— (where d is an integer 1 to 4 inclusive),
—(CH
2
)
d
NHCO(CH
2
)
e
— (where e is an integer 1 to 4 inclusive) and —(CH
2
)
d
NHCO(CH
2
)
e
OCH
2
—.
The reactive functional group represented by Z in compounds of formula (1) may be any group capable of reacting with a thiol, amino, carboxyl, hydroxyl, aldehyde, aromatic or heteroaromatic group. Aromatic groups include, for example, phenolic groups. Heteroaromatic groups include for example imidazolyl groups.
Thus, Z may be, for example,
(i) a halogen atom (as for example a chlorine, bromine or iodine atom),
(ii) a group selected from —SH, —NH
2
, hydrazino (—NHNH
2
) or a derivative thereof, (for example —N(CH
3
)NH
2
, —NHCONHNH
2
, —NHCSNHNH
2
, or phenyl hydrazino),
(iii) —NCO, —NCS, —COR
10
in which R
10
is a halogen atom (as for example a chlorine or bromine atom), N
3
, C
1-6
alkoxy, (as for example methoxy), C
6-12
aryloxy (as for example nitrophenyloxy or dinitrophenyloxy), imidyloxy (as for example succinimidylo

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